Interferon‐γ‐inducible protein 10 augments atopic dermatitis via amplifying Th2 immune response
Authors: Young‐Ae Choi, Namkyung Kim, Na‐Hee Jeong, Taeg Kyu Kwon, Jin Seon Bang, Yong Hyun Jang, Sang‐Hyun Kim
Journal: Allergy (2023)

To the Editor Interferon-γ-inducible protein 10 (IP-10; CXCL10) is a T-helper 1 (Th1)-associated chemokine.1 However, IP-10 can reportedly be involved in Th2-mediated inflammation in allergic asthma,2 and elevated levels in the lesions and serum of atopic dermatitis (AD) patients correlating to disease severity.3-5 These findings indicate the potential role of IP-10 in this Th2-dominant skin disease. Therefore, this study aims at elucidating the significance, specificity, and mechanism underlying IP-10 expression in AD pathogenesis. House dust mite (HDM) is one of the causative antigens of extrinsic AD,6 causing epidermal barrier disruption via several mechanisms. To assess the impact of HDM exposure on IP-10 expression, we analyzed lesional tissues of AD patients categorized according to HDM-specific IgE levels (Table S1), along with 2,4-dinitrochlorobenzene/Dermatophagoides farinae extract (DNCB/DFE)-induced (Figure S1A) and DFE-induced (Figure S1B) mouse AD models. IP-10 expression was remarkably elevated in the lesional tissues, particularly the epidermis, of high level-HDM-sensitized AD patients (Figure 1A) and the DNCB/DFE-induced AD models (Figure 1B). The duration of HDM exposure in the AD model using DFE with/without DNCB progressively increased IP-10 expression in skin tissues but remained unaffected in the serum (Figure 1C). Furthermore, IP-10 expression in the epidermis was attributable to the HDM-specific activation depending on the differentiation of epidermal keratinocytes (Figures S1C–F). To comprehend the function of IP-10 in AD pathogenesis, DNCB/DFE-applied AD model with or without recombinant IP-10 (rIP-10) injection was induced in both ears of wild-type (WT) and IP-10 knockout (IP-10-KO) mice (Figure S2A). The body weight in both models or spleen weight by rIP-10 injection remained unaltered (Figures S3A and B). Compared with WT AD mice, lesion characteristics, including erythema, edema, scaling, and ear thickening, were ameliorated in IP-10-KO and exacerbated in rIP-10-injected mice (Figures 1D and S3C); histopathological changes, including dermal and epidermal thickness, and mast cell infiltration in the lesioned area showed similar results (Figures 1E and S3D). The lesional IP-10 level variations regulated the representative mediators of Th1 and Th2 immune responses: for Th1, CD4+/IFN-γ+ Th cell proportions in auricular lymph nodes, serum IgG2a, and the lesional Il-12a and Il-1β gene expression (Figures 1F, H, J, and L), while for Th2, CD4+/IL-4+ Th cell proportions in auricular lymph nodes, serum IgE, and the lesional Il-4 gene expression (Figures 1G, I, K, and M). Additionally, to evaluate the direct and specific effects of IP-10 on Th2 immune response during AD development, analysis of the results at 3 and 5 weeks after injection of rIP-10 into DNCB/DFE-applied KO mice revealed a significant increase in the mediators of Th2 immunity compared to Th1, and evident AD phenotypes (Figure S4) Subsequently, we investigated the mechanism of action underlying IP-10-induced Th2 immune responses using the tissues of the rIP-10-injected AD model and various rIP-10-treated Th2 cell lines. The co-relation of IP-10 expression and the dermal infiltration of CD4+ lymphocytes indicating Th cells in AD lesions was verified in a preliminary study (Figure S5). Similar to CD4+ cells distribution, CD4/pSTAT6 double-positive cells indicating Th2 lymphocytes were significantly increased in the rIP-10-injected group compared to the PBS-injected group in both WT and KO AD mice (Figures 2A and B). rIP-10 treatment at the cellular level escalated the differentiation of local lymph node-derived naïve CD4+ T lymphocytes into CD4+/IL-4+ Th2 lymphocytes (Figure 2C). Moreover, The treatment of rIP-10 increased IL-4 expression in Jurkat-E6.1 (naïve CD4+ T lymphocyte cell line) and CCRF-CEM (Th2 cell line) cells via the transcriptional activity of GATA3, NFAT1, and STAT6 without affecting cell proliferation (Figures 2D-K) The development and progression of AD are regulated by reciprocal interaction between resident cells and recruited inflammatory cells through intricate mechanisms. Epidermal keratinocyte-derived secretory molecules can influence these various lesional cells. The role of IP-10 in AD presumably extends beyond affecting Th2 immune response by regulating Th2 cell function, and its thorough comprehension warrants extended studies in large cohorts. Nevertheless, our study discovered a novel mechanism of action of epidermal keratinocyte-derived IP-10 underlying the differentiation and activation of Th2 lymphocytes, which could serve as a potential therapeutic target against relapsing AD Young-Ae Choi: Designed and performed the research, analyzed the data, and wrote the paper. Namkyung Kim: Performed research. Na-Hee Jeong: Performed research. Taeg Kyu Kwon: Analyzed data. Jin Seon Bang: Contributed to new reagents or analytic tools. Yong Hyun Jang: Drafted the article and revised it critically for important intellectual content; provided approval of the version to be submitted. Sang-Hyun Kim: Drafted the article and revised it critically for important intellectual content; provided approval of the version to be submitted. This research was supported by a National Research Foundation of Korea grant funded by the Korean Government (2019R1A2B5B01069444, 2022M3A9G8018189, 2021R1A5A2021614, 2020R1A2C1010962, and 2020M3A9D3038894). The authors declare no conflicts of interest. The data that supports the findings of this study are available in the supplementary material of this article Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Figure S6. Data S1. Data S2. Data S3. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.